Metabolism of Clozapine by cDNA-Expressed Human Cytochrome P450 Enzymes
作者： Kristian Linnet , Ole V. Olesen
DOI:
关键词: Metabolism 、 CYP2E1 、 Cytochrome P450 、 Biochemistry 、 CYP3A4 、 Demethylation 、 Enzyme 、 Biology 、 CYP1A2 、 Isozyme
摘要: The metabolism of clozapine was studied in vitro using cDNAexpressed human cytochrome P450 (CYP) enzymes 1A2, 3A4, 2C9, 2C19, 2D6, and 2E1. CYP1A2, 2D6 were able to N-demethylate clozapine. N-Oxide formation exclusively catalyzed by CYP3A4. CYP2E1 did not metabolize With regard quantitative relationships, displayed KM values ranging from 13 25 mM, whereas CYP3A4 had a 5‐10 times higher value. CYP2C19 the highest Vmax (149‐366 mol/hr/mol CYP). Taking into account typical relative distribution amounts CYP liver, simulation study suggested that at therapeutic concentrations each accounted for about 35% metabolism. At toxic concentrations, importance increased.
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